U.S. patent application number 12/681740 was filed with the patent office on 2010-09-02 for method of producing emulsion or dispersion and food, skin external preparation and drug containing emulsion or dispersion obtained by the production method.
This patent application is currently assigned to FUJIFILM CORPORATION. Invention is credited to Jun Arakawa, Hideharu Nagasawa, Tomohide Ueyama.
Application Number | 20100221297 12/681740 |
Document ID | / |
Family ID | 40526123 |
Filed Date | 2010-09-02 |
United States Patent
Application |
20100221297 |
Kind Code |
A1 |
Arakawa; Jun ; et
al. |
September 2, 2010 |
METHOD OF PRODUCING EMULSION OR DISPERSION AND FOOD, SKIN EXTERNAL
PREPARATION AND DRUG CONTAINING EMULSION OR DISPERSION OBTAINED BY
THE PRODUCTION METHOD
Abstract
A water-soluble organic solvent solution containing a natural
ingredient that has been extracted from a natural animal or plant
using a water-soluble organic solvent and an aqueous solution are
passed through respective microflow channels each of which has a
cross-sectional area at a narrowest portion of from 1 .mu.m.sup.2
to 1 mm.sup.2; and thereafter mixed by a counter collision.
Preferably, the water-soluble organic solvent is removed after the
mixing. Also provided are a food, a skin external preparation, and
a drug, each of which contains an emulsion or dispersion obtained
thereby.
Inventors: |
Arakawa; Jun;
(Ashigarakami-gun, JP) ; Ueyama; Tomohide;
(Minami-Ashigara-shi, JP) ; Nagasawa; Hideharu;
(Minami-Ashigara-shi, JP) |
Correspondence
Address: |
SUGHRUE MION, PLLC
2100 PENNSYLVANIA AVENUE, N.W., SUITE 800
WASHINGTON
DC
20037
US
|
Assignee: |
FUJIFILM CORPORATION
Minato-ku, Tokyo
JP
|
Family ID: |
40526123 |
Appl. No.: |
12/681740 |
Filed: |
September 29, 2008 |
PCT Filed: |
September 29, 2008 |
PCT NO: |
PCT/JP2008/067616 |
371 Date: |
April 5, 2010 |
Current U.S.
Class: |
424/401 ;
366/162.4; 366/341; 424/520; 424/725; 426/431; 426/654;
977/902 |
Current CPC
Class: |
B01F 13/0059 20130101;
A61K 8/9728 20170801; A61P 43/00 20180101; B01F 5/0256 20130101;
A61K 8/9711 20170801; A61Q 19/00 20130101; A61K 2800/21 20130101;
A61K 8/06 20130101; B01F 3/0811 20130101; A61K 8/9733 20170801;
A61K 8/9722 20170801; A23L 33/10 20160801; A61K 8/9789 20170801;
A61K 8/9717 20170801; A61K 9/107 20130101; A61K 8/9767 20170801;
A61K 8/9794 20170801; A61K 8/9771 20170801 |
Class at
Publication: |
424/401 ;
424/725; 424/520; 426/654; 426/431; 977/902 |
International
Class: |
A61K 8/06 20060101
A61K008/06; A61K 36/00 20060101 A61K036/00; A61K 35/12 20060101
A61K035/12; A61P 43/00 20060101 A61P043/00; A61Q 19/00 20060101
A61Q019/00; A23L 1/28 20060101 A23L001/28 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 3, 2007 |
JP |
2007-260335 |
Claims
1. A method of producing an emulsion or a dispersion, the method
comprising: passing an aqueous solution and a water-soluble organic
solvent solution containing a natural ingredient that has been
extracted from a natural animal or plant using a water-soluble
organic solvent through respective microflow channels each of which
has a cross-sectional area at a narrowest portion of from 1
.mu.m.sup.2 to 1 mm.sup.2; and thereafter mixing the water-soluble
organic solvent solution and the aqueous solution by counter
collision.
2. The method of producing an emulsion or a dispersion according to
claim 1, wherein a volume average particle diameter of oil droplet
particles or dispersed particles in the obtained emulsion or
dispersion is in a range of from 1 nm to 100 nm.
3. The method of producing an emulsion or dispersion according to
claim 1, wherein a ratio (Vo/Vw) of a flow speed (Vo) of the
water-soluble organic solvent solution to a flow speed (Vw) of the
aqueous solution is from 0.05 to 5 during the mixing.
4. The method of producing an emulsion or dispersion according to
claim 1, wherein a flow rate of the water-soluble organic solvent
solution is from 1 ml/min to 70 ml/min.
5. The method of producing an emulsion or dispersion according to
claim 1, wherein a flow rate of the aqueous solution is from 10
ml/min to 500 ml/min.
6. The method of producing an emulsion or dispersion according to
claim 1, further comprising, after the mixing, removing the
water-soluble organic solvent from the obtained emulsion or
dispersion.
7. The method of producing an emulsion or dispersion according to
claim 1, wherein the water-soluble organic solvent solution
contains at least one nonionic surfactant having an HLB value of
from 10 to 16.
8. The method of producing an emulsion or dispersion according to
claim 1, wherein the water-soluble organic solvent is ethanol or a
mixture of ethanol and water.
9. The method of producing an emulsion or dispersion according to
claim 1, wherein the natural ingredient is a functional food
ingredient.
10. A food comprising an emulsion or dispersion produced by the
production method according to claim 9.
11. The method of producing an emulsion or dispersion according to
claim 1, wherein the natural ingredient is a skin external
preparation ingredient.
12. A skin external preparation comprising an emulsion or
dispersion produced by the production method according to claim
11.
13. The method of producing an emulsion or dispersion according to
claim 1, wherein the natural ingredient is a pharmaceutical
ingredient.
14. A drug comprising an emulsion or dispersion produced by the
production method according to claim 13.
Description
TECHNICAL FIELD
[0001] The present invention relates to a method of producing an
emulsion or a dispersion, and a food, a skin external preparation
and a drug each of which contains an emulsion or dispersion
obtained by the production method.
BACKGROUND ART
[0002] Active ingredients have been extracted from natural animals
and plants using water-soluble organic solvents such as alcohols,
and have been used in foods and drinks as food additives, or added
to cosmetics as functional cosmetics. With the coming of health
fad, extraction from various natural materials has widely conducted
lately. Extraction of active ingredients from materials that were
wasted until recently, such as from banana leaves, leftover
portions of citrus and outer skins of onion, is also conducted
using alcohols.
[0003] Usually, natural active ingredients, which are extracted
with water-soluble organic solvents such as alcohols, are
thereafter isolated in the form of powders, oils or waxes of the
natural active ingredients through the processes of removal of the
organic solvents from the extract liquids, concentration and
drying, and are used as raw materials of foods or drinks. However,
many of the active ingredients do not readily dissolve in water.
Therefore, use of the active ingredients in aqueous foods, aqueous
drinks, and aqueous cosmetics with superior tactile sensation
requires subjecting the active ingredients to processes of
emulsification or dispersion after dissolving the active
ingredients in other solvents, oils or fats or after melting the
active ingredients themselves at high temperatures. As a result,
the cost of the processes has been necessarily high. In particular,
achievement of effective absorption of the active ingredients
requires a decrease of the size of the oil droplets of the active
ingredients to 1 .mu.m or less, and a great amount of
emulsification energy has been required therefor. Further, there
are cases in which the active ingredients deteriorate during the
process of once drying the active ingredients and redissolving or
melting them. Therefore, a decrease in active ingredient amount and
side effects caused by deteriorated ingredients have sometimes been
problematic.
[0004] In view of the above, the present inventors tried to
emulsify and disperse an extract liquid as it is; that is, an
aqueous organic solvent containing an active ingredient is
emulsified and dispersed, with an emulsifying agent, in an aqueous
phase according to usual emulsification methods. Here, the usual
emulsification methods are methods using a mechanical force, i.e.,
methods of dividing an oil droplet by applying a strong shear force
from the outside. A most common mechanical force is a high-speed
high-shear agitation apparatus. Homomixers, dispermixers, and
ultramixers, which are agitation apparatuses of this kind, are
commercially available. Other apparatuses that can apply a strong
shear force and that are useful for atomization include
high-pressure homogenizers, and various kinds thereof are
commercially available. Ultrasonic homogenizers, which are
relatively energy-efficient dispersing apparatuses, are also used
frequently as experiment devices.
[0005] When an aqueous organic solvent containing an active
ingredient is emulsified and dispersed, using an emulsifying agent,
in an aqueous phase according to the usual emulsification methods
using an emulsification apparatus such as a high-shear agitation
apparatus, a high-pressure homogenizer, or a ultrasonic
homogenizer, it is very difficult to emulsify a system containing a
large amount of water-soluble organic solvent, and an average
particle diameter of 1 .mu.m or less cannot be achieved. The
resultant particle diameter distribution is broad, and coarse
particles separate out in a short time, causing problems in the
preservation properties of foods and cosmetics. When natural active
ingredients that are insoluble in water are incorporated into
aqueous foods or aqueous cosmetics, it is often requested to finely
emulsify and disperse the natural active ingredients, in
consideration of digestion, absorption, stability against
sedimentation and separation through floating with time,
transparency of the appearance, and the like of the active
ingredients. In general, an average particle diameter of 200 nm or
less is required for fulfilling most of the requests.
[0006] Further, another emulsification method of continuously
producing microparticles or nano-particles of a natural substance
using a micromixer is disclosed in European Patent No. 1180062;
granulation of a natural active ingredient is attempted by
respectively introducing, into a microflow channel, a
particle-forming phase of a natural active ingredient and an
aqueous phase whose main component is water, and allowing the
respective phases to form layered liquids and periodically mix with
each other. However, the average particle diameter of the obtained
particles is never below 1000 nm, which is clearly far from a
target particle diameter of 200 nm.
DISCLOSURE OF THE INVENTION
The Problem to be Solved by the Invention
[0007] The present invention aims at provision of a fine emulsion
or dispersion of a natural ingredient that is extracted from an
animal or plant using a water-soluble organic solvent, and that is
in a state in which deterioration of the quality of the natural
ingredient is extremely small.
Means for Solving the Problem
[0008] The present invention has been made in view of the above
circumstances, and provides a method of producing an emulsion or an
dispersion, and a food, a skin external preparation and a drug each
of which contains an emulsion or dispersion obtained by the
production method.
[0009] A first aspect of the invention provides a method of
producing an emulsion or a dispersion, the method comprising:
[0010] passing an aqueous solution and a water-soluble organic
solvent solution containing a natural ingredient that has been
extracted from a natural animal or plant using a water-soluble
organic solvent through respective microflow channels each of which
has a cross-sectional area at the narrowest portion of from 1
.mu.m.sup.2 to 1 mm.sup.2; and
[0011] thereafter mixing the water-soluble organic solvent solution
and the aqueous solution by counter collision.
[0012] A second aspect of the invention provides a food comprising
an emulsion or dispersion obtained by the production method
described above, wherein the natural ingredient is a functional
food ingredient.
[0013] A third aspect of the invention provides a skin external
preparation comprising an emulsion or dispersion obtained by the
production method described above, wherein the natural ingredient
is a skin external preparation ingredient.
[0014] A fourth aspect of the invention provides a drug comprising
an emulsion or dispersion obtained by the production method
described above, wherein the natural ingredient is a pharmaceutical
ingredient.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] FIG. 1 is an exploded perspective view of a microdevice as
an example of a micromixer.
BEST EMBODIMENT FOR CARRYING OUT THE INVENTION
[0016] The method of producing an emulsion or a dispersion
according to the invention comprises:
[0017] passing an aqueous solution and a water-soluble organic
solvent solution containing a natural ingredient that has been
extracted from a natural animal or plant using a water-soluble
organic solvent through respective microflow channels each of which
has a cross-sectional area at the narrowest portion of from 1
.mu.m.sup.2 to 1 mm.sup.2; and
[0018] thereafter mixing the water-soluble organic solvent solution
and the aqueous solution by counter collision.
[0019] In the production method, a natural ingredient that has been
extracted using a water-soluble organic solvent as an extracting
liquid is mixed, in a state of a post-extraction solution, i.e., as
the water-soluble organic solvent solution, with an aqueous
solution. Therefore, it is not necessary to use the natural
ingredient in a post-drying state or in a re-dissolved state after
drying. Accordingly, deterioration of the quality of the natural
ingredient, such as thermal deterioration due to a drying process,
can be minimized. Further, since a water-soluble organic solvent
solution containing the natural ingredient, which serves as an oil
phase, is mixed with an aqueous solution by counter collision using
microchannels, a fine emulsion or a fine dispersion can be
obtained.
[0020] The term "dispersion" as used in the invention mainly refers
to a "dispersion of a solid" or "dispersion of a solid matter" in
which a solid that is formed as a result of emulsion, dispersing,
or a subsequent process is dispersed in a dispersion medium.
[0021] In the invention, the scope of the term "process" not only
includes an independent process, but also includes a process that
cannot be clearly distinguished from other processes as long as
expected actions of the process are achieved.
[0022] Expressions indicating numerical ranges in the invention
include the upper and lower limit values.
[0023] The term "natural ingredient" used in the invention refers
to an ingredient that is isolated from an animal or plant by an
extraction procedure using an organic solvent. The term
"extraction" refers to a chemical isolation procedure, in which a
liquid or solid raw material is contacted with a solvent so as to
selectively isolate an ingredient that is contained in the raw
material and soluble in the solvent, from ingredients that are
insoluble or hardly soluble in the solvent. The extraction
procedure in the invention is within the scope of the general
extraction procedure described above.
[0024] The animal or plant raw materials that can be used in the
invention are not particularly limited. Supposing that the emulsion
or dispersion of the invention is used mainly in health foods or
health drinks as the final products, plant materials are preferable
compared to animal materials from the viewpoints of odor, taste and
healthy image. With respect to the parts of plants, any parts
including leaf, stem, peel and fruit can be used as the material.
Furthermore, algae, hyphae, yeasts and fungi are preferable as the
material for the present invention.
[0025] Examples of land plants raw material include Angelica
keiskei, Phaseolus angularis, Gynostemma pentaphyllum, alfalfa,
aloe, ginkgo, Urtica thunbergiana, Azadirachta indica, Indian
gooseberry, Foeniculum vulgare (fennel), Curcuma longa (turmeric),
Prunus mume, Citrus unshu, Echinacea purpurea, Acanthopanax
senticosus, Sambucus nigra (elder), Astragalus membranaceus,
Plantago asiatica, Onopordum, Hordeum vulgare (barley), green
barley leaf, Abelmoschu esculentus, Panax ginseng, oat wheat, Olea
europaea (olive), Diospyros kaki, Curcuma zedoaria (zedoary),
Valeriana fauriei, Chamomilla recutita, Paullinia cupana,
Glycyrrhiza glabra (licorice), Garcinia cambogia, Aloe arborescens,
Gymnema sylvestre, Uncaria tomentosa (cat's claw), Allium
victorialis, Psidium guajava, Lycium chinense, Pueraria lobata,
Sasa veitchii, Orthosiphon aristata (Cumisctin), Vaccinium
macrocarpon (cranberry), Citrus grandis (grapefruit), Morus alba
(mulberry), Cinnamomum cassi, Laurus nobilis, Brassica oleracea
var. acephala (kale), Gentiana lutea, Kothala himbutu (Salacia
reticulata), Coffea arabica (coffee), Sesamum indicum (sesame),
Oryza sativa (rice), Triticum vulgare (wheat), Amorphophallus
konjac (elephant foot), Punica granatum (pomegranate), Crocus
sativus (saffron crocus), Crataegus cuneata, Panax notoginseng,
Perilla ocymoides [Perilla frutenscens acuta], Pterocarpus
santalinus (Dalbergia cochinchinensis), Jasminum officinale
(jasmine), Betula platyphylla, Zingiber officinale (ginger),
Equisetum arvense (field horsetail), Stevia rebaudiana, Hypericum
perforatum (St. John's wort), Crataegus oxyacantha, Prunus
domestica (prune), Taraxacum officinale, Aesculus hippocastanum
(marronier), Polygonum fagopyrum [Fagopyrum esculentum], Glycine
soja (soybean), Citrus aurantium (better orange), Thymus vulgaris
(thyme), Tamarindus indica, Allium cepa (onion), Aralia elata
Seemann (Japanese angelica tree), chaste tree, Thea sinensis (tea),
Cynara scolymus (artichoke), camellia, Centella asiatica, Rubus
suavissimus, Capsicum annuum, Houttuynia cordata, Eucommia
ulmoides, Solanum lycopersicum (tomato), Daucus carota sativa
(carrot), Phoenix dactylifera (date), Allium sativum (garlic),
Serenoa repens (Saw palmetto), Tabebuia impetiginosa (Pau d'arco),
Nelumbo nucifera, Carum petroselinum (parsley), Coix lacryma-jobi
ma yuen (Job's tears), Capsicum annuum cv (paprika), rose, Fucus
vesiculosus, Vaccinium myrtitllus, Eriobotrya japonica (loquat),
Tussilago farfara (coltsfoot), Vitis binefera (grape), black
cohosh, blueberry, propolis, Carthamus tinctorius (safflower),
Spinacia oleracea (spinach), Peumus boldu, Lepidium meyenii (maca),
macadamia nuts, Manchurian wild rice, pine, Ilex paraguariensis
(mate), Tagetes spp. (marigold), mandarin orange, Acer nikoense
Maximowicz (Nikko Maple), Oenothera biennis (evening primrose),
Melissa officinalis (melissa), Melilotus officinalis Lam, Corchorus
olitorius L. (Mulukhiyya), yucca, Artemisia princeps (mugwort),
Apocynum venetum L. (Luobuma), Lavandula angustifolia (lavender),
Pyrus malus (apple), Litchi chinensis (lychee), Citrus medica
lemonum (lemon), Rosmarinus offisinalis (rosemary), Walteria
indica, moss plants, fern plants and the like, but the invention is
not limited thereto.
[0026] With respect to algae, all photosynthetic algae generating
oxygen can be used. Examples of the algae include cyanobacteria,
Prochlorophyta, Glaucophyceae, Rhodophyceae, Prasinophyceae,
Ulvophyceae, Chlorophyceae, trebouxiophyceae, Charophyceae,
Cryptophyceae, Chlorarachniophyceae, Euglenophyceae, Dinophyceae,
Chrysophyceae, Raphidophyceae, Eustigmatophyceae, Xanthophyceae,
Phaeophyceae, Cacillariophyceae, Dictyochophyceae, Pelagophyceae,
Haptophyceae and the like. Among these algae, spirulina belonging
to Cyanophyceae; Haematococcus belonging to Chlorophyceae; and
Nemacystus, Laminaria, and Undaria (seaweed) belonging to
Phyaeophyceae are particularly important materials.
[0027] Various examples are included in hyphae, yeasts and fungi.
Examples thereof include Agaricus, yeasts, Lentinus edodes (Berk.)
Sing (shiitake), Agaricus bisporus (champignon), Cordyceps sinensis
(Cordyceps), Bacillus subtilis (Hay bacillus), Bifidobacteria,
Monascus purpureus (Red yeast rice), Tremella fuciformis, Grifola
frondosa (Gray-maitake), bisporus (common mushroom), Phellinus
linteus, Hericium erinaceus, Ganoderma lucidum. Karst (Reishi) and
the like, but the invention is not limited thereto.
[0028] Various ingredients over a broad range can be extracted from
these natural materials. Typical examples thereof include lipid
ingredients contained in animals and plants. Examples of the lipid
ingredients include fatty acids, glycerides, complex lipids,
terpenoids, steroids, prostaglandins and the like.
[0029] Among these lipid ingredients, examples of the active
ingredient include linoleic acid, .gamma.-linolenic acid,
arachidonic acid, .alpha.-linolenic acid, eicosapentaenoic acid,
docosahexaenoic acid, .gamma.-aminobutyric acid, thioctic acid and
the like. Examples of the glycerides include monoacylglycerol,
diacylglycerol and triacylglycerol. Examples of the complex lipids
include phospholipids such as phosphatidic acid,
phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine
and phosphatidylinositol; sphingo lipids such as sphingosine and
sphingomyelin; and glycolipids such as monogalactosyl glyceride and
glucosyl ceramide.
[0030] Examples of the active ingredients of terpenoids include
monoterpenes such as linalool, citronellal, myrcene, limonene,
pinene, menthol, cineol, camphor, longifolene, cedrol and
caryophyllene; diterpenoids such as phytol, abietic acid, kaurene
and gibberellin; triterpenoids such as squalene and dammarenediol;
tetraterpenoids typified by carotenoid pigments; and polyterpenoids
such as gutta-percha, vitamin K2, ubiquinone and vitamin K1. Among
these substances, carotenoid pigments may attract particular
attention owing to the antioxidative activity thereof. Typical
examples of the carotenoid pigments include astaxanthin, lycopene,
zeaxanthin, lutein, capsanthin, fucoxyanthin, .alpha.-carotene and
.beta.-carotene.
[0031] Examples of the active ingredients of the steroids include
sterols such as squalene, cholesterol, ergosterol, stigmasterol,
dehydrocholesterol, cholecalciferol (vitamin D3) and 25-hydroxy
vitamin D3; sex hormones such as testosterone, androsterone,
progesterone, estrogen and estradiol; adrenocortical hormones such
as cortisone and dexamethasone; cardiac glycosides such as
digitoxigenin, digoxigenin and gitoxigenin; steroid sapogenins such
as diosgenin and cortisone; and bile acids such as cholic acid and
deoxycholic acid.
[0032] One of important natural ingredients other than lipid
ingredients is polyphenol. Polyphenol is a generic name for plant
ingredients having two or more phenolic hydroxyl groups within a
molecule. Polyphenol constitutes a plant pigment and a bitter
ingredient formed by photosynthesis, and has particularly excellent
antioxidation activity. Examples of polyphenols include flavonoids,
chlorogenic acids, gallic acids, ellagic acids, lignans, curcumins
and coumarins. Examples of flavonoids include isoflavones such as
genistein and daizen; flavonols such as quercetin, kaempferol,
myricetin and rutin; flavanones such as hesperidin and naringin;
anthocyanins such as cyanidin and delphinidin; flavanols such as
epicatechin, epigallocatechin, epicatechin gallate and theaflavin;
and flavones such as chrysin, apigenin and luteolin. Many of
polyphenols have attracted public attention as ingredients of
health foods and cosmetics, and examples of such polyphenols
include galangin, fisetin, chalcone, puerarin and resveratrol.
[0033] Other natural ingredients include alkaloids, which are
particularly useful in the medicinal field. Examples of the
alkaloids include aconitine, atropine, ephedrine, caffeine,
capsaicin, quinine, curare, cocaine, colchicine, scopolamine,
strychnine, solanine, taxine, theophylline, dopamine, nicotine,
vinca, berberine, morphine, lycorine and the like.
[0034] Furthermore, other natural ingredients include shogaol and
gingerol extracted from ginger, allyl isothiocyanate that is
contained in horseradish or mustard, and allicin, alliin and
scordinine contained in garlic, and the like.
[0035] The water-soluble organic solvent in the present invention,
which serves as an oil phase containing natural component, is used
for mixing with a below described aqueous solution. The
water-soluble organic solvent is also a main component of the
extracting liquid with which the natural component is extracted.
That is, in the invention, the natural integrant is used to be
mixed with the aqueous solution in a state where the natural
integrant is extracted with the extracting liquid containing the
water-soluble organic solvent as the main component.
[0036] The term "water-soluble organic solvent" to be used in the
invention refers to an organic solvent which has a solubility in
water (at 25.degree. C.) of 10% by mass or more. From the viewpoint
of the stability of the obtained emulsion or dispersion, the
solubility in water is preferably 30% by mass or more, and more
preferably 50% by mass or more.
[0037] The water-soluble organic solvent may be used singly or as a
mixed solvent of plural water-soluble organic solvents. Further,
the water-soluble organic solvent may be used as a mixture with
water. When the water-soluble organic solvent is used as the
mixture with water, the content of the water-soluble organic
solvent in the mixture is preferably 50% by volume or more, and
more preferably 70% by volume or more.
[0038] Examples of the water-soluble organic solvent include
methanol, ethanol, 1-propanol, 2-propanol, 2-butanol, acetone,
tetrahydrofuran, acetonitrile, methyl ethyl ketone, dipropylene
glycol monomethyl ether, methyl acetate, methyl acetoacetate,
N-methylpyrrolidone, dimethyl sulfoxide, ethylene glycol,
1,3-butanediol, 1,4-butanediol, propylene glycol, diethylene
glycol, triethylene glycol and the like, and mixtures thereof.
Among these, ethanol, propylene glycol and acetone are preferable,
and ethanol and a mixture of ethanol with water are more preferable
when the application thereof is limited to foods.
[0039] The method of extracting a natural ingredient from the
above-described animal and plant raw materials using a
water-soluble organic solvent may be a conventional method. Since
solid raw materials obtained by finely crushing raw materials such
as dried plants are often used, solid-liquid extraction apparatuses
are mainly used. In experiments, a simple method of performing
extraction procedures in a beaker or the like while stirring and
maintaining a constant temperature, or a soxhlet extractor or the
like, may be used. Examples of solid-liquid extraction apparatuses
that are used industrially include permeation through-flow
extractors, and examples thereof include a battery extractor, which
is a batch-type extractor, and a Bollman extractor, a Rotcel
extractor, a Lurgi extractor, and a Kennedy extractor, which are
continuous-type extractors. As a solid-dispersing apparatus, a
Pachuca tank extractor, a bonotto extractor, or the like may be
used.
[0040] In the invention, it is preferable that the animal, plant,
alga, yeast, bacterium, or the like to be used for extraction is
sufficiently washed with water, and then directly, or after drying,
subjected to a pre-treatment which is a physical crushing treatment
such as a ball milling, frost shattering, compression crushing or
ultrasonic treatment, an enzymatic treatment, or the like. When
extraction from a wet material is performed using an organic
solvent, incorporation of contaminants is severe, and extraction
ratio is decreased in every case. Therefore, solvent extraction
from dried microbial body is industrially preferable.
[0041] Extraction employed in the invention is conducted
representatively at a temperature that is sufficiently high for
causing significant extraction and that is lower than a temperature
at which the properties of the active ingredient to be extracted is
adversely affected (or a temperature higher than a reasonable
reflux temperature of the selected extraction solvent). The
extraction temperature is generally in a range of from 0.degree. C.
to 300.degree. C., but may be a temperature that is higher or lower
than this range. In general, the extraction temperature depends on
the boiling or freezing characteristics of the extraction solvent
or of the solution. Basically, a higher temperature results in a
higher extraction speed. Therefore, a moderate temperature is
preferable for achieving an economical extraction speed. A usual
extraction temperature is from 20.degree. C. to 68.degree. C., and
the extraction temperature is preferably from about 20.degree. C.
to about 50.degree. C.
[0042] Selection of the extraction solvent depends on,
representatively, factors such as chemical properties of the active
ingredient to be extracted, dissolution properties, boiling point,
and freezing point. The extraction solvent may be selected
preferably from the water-soluble organic solvents described above.
An alcohol, such as ethanol or n-propyl alcohol, is a favorable
extraction solvent, regardless of whether the alcohol is undiluted
or diluted with water. Ethanol is a particularly preferable
extraction solvent.
[0043] When the extraction solvent to be used is, for example,
ethanol, extraction is conducted for from about 30 minutes to about
2 hours using the extraction solvent in an amount that is from 3
times to 100 times greater (by weight) than that of the raw
material to be extracted. After the active ingredient is eluted
into the solvent, extraction residue is removed by filtration, as a
result of which an extract liquid is obtained. Thereafter, the
extract liquid is subjected to one or more treatments such as
dilution, concentration, or purification according to a common
method, whereby an ethanol solution of the active ingredient
according to the invention is obtained.
[0044] The residue of the animal or plant raw material remaining
after extraction of the natural ingredient can be removed using a
method whereby a solid component and a liquid component of the
immersion liquid can be separated. The method may be, for example,
any of filtration, centrifugal separation, sedimentation by being
left to stand still, or a combination thereof. When conducting
filtration, the filtration manner is not limited. For example, the
filtration may be performed by natural dropping, or may be
performed under pressure control such as vacuum filtration. The
filter portion may be any of a paper filter, a membrane filter, a
cloth filter, a charcoal filter, a hollow fiber membrane filter, a
micro filter, a CELITE filter, a diatomite filter, or a combination
thereof. The filter portion may have either a single layer or
multiple layers. When using a multilayer filter, the multilayer
filter may be composed of plural layers that may the same or
different. Further, the layers of the multilayer filter are not
required to be stacked vertically or horizontally, as long as the
layers are arranged such that the liquid component is allowed to go
through the respective layers. For example, when plural columns
filled with filter component(s) are connected via tubes so as to
enable filtration, the respective layers may be separated from each
other.
[0045] When conducting centrifugal separation, the manner of
separating the solid component and the liquid component is not
limited. For example, the filtration manner may be a manner in
which an immersion liquid is introduced into a porous tube, the
porous tube is centrifuged in a centrifuge, and an extract liquid
discharged from the pores is collected, or may be a manner in which
an immersion liquid is introduced into an imperforate tube and an
extract liquid as a supernatant is collected after centrifugation.
The gravitational acceleration of the centrifugation (G) is not
particularly limited as long as the liquid component and the solid
component can be separated to a certain degree.
[0046] When the extract liquid of the natural ingredient of the
invention is contacted with at least one selected from activated
carbon, acid clay, or activated earth before removing insoluble
solid matter from the extract liquid by filtration or other
methods, removal of the insoluble solid matter becomes extremely
easy. For example, when removing the insoluble solid matter by
filtration, the number of filtration stages can be minimized, for
example to once. The activated carbon to be used may be selected,
without particular restrictions, from activated carbons generally
utilized in industries. Examples of activated carbons that may be
used include commercial products such as ZN-50 (manufactured by
Hokuetsu Carbon Industry Co., Ltd.), KURAREY COAL GLC, KURAREY COAL
PK-D, and KURAREY COAL PW-D (manufactured by Kurarey Chemical Co.,
Ltd.), and SHIRASAGI AW50, SHIRASAGI A, SHIRASAGHI M, and SHIRASAGI
C (manufactured by Takeda Pharmaceutical Company Limited). The pore
volume of the activated carbon is preferably from 0.01 to 0.8 mL/g,
and the specific surface area thereof is preferably from 800 to
1300 m.sup.2/g. The amount of the activated carbon is preferably
from 0.5 to 5 parts by mass relative to 100 parts by mass of the
ethanol solution.
[0047] The content of the natural ingredient in the water-soluble
organic solvent solution in the invention varies with the types of
the raw material and the natural ingredient, and may generally be
from 0.01% by mass to 30% by mass, preferably from 0.1% by mass to
10% by mass, relative to the total mass of the water-soluble
organic solvent solution, from the viewpoints of the efficiency of
the production of an emulsion or dispersion and the stability of
the emulsion or dispersion.
[0048] The water-soluble organic solvent solution may include, in
addition to the natural ingredient, other ingredients as necessary.
Examples of the other ingredients include oil ingredients such as
hydrogenated oils and fats and silicone oils, and surface active
compounds such as nonionic surfactants, ionic surfactants,
synthetic phospholipids, and synthetic ceramides.
[0049] The aqueous solution in the invention, i.e., the aqueous
phase, is an aqueous solution whose main component is water.
[0050] The aqueous solution may include one or more of a nonionic
surfactant, an ionic surfactant, a water-soluble salt, a
saccharide, a polysaccharide, a protein, a pH adjuster, an
antioxidant, a preservative, a colorant, a perfume, or the like,
such as those described below.
[0051] Examples of the ionic surfactant include an alkylsulfonate,
an alkylsulfate, a monoalkylphosphate, a fatty acid salt, and
lecithin. Examples of the salt include sodium chloride, sodium
citrate, and sodium ascorbate. Examples of the saccharide include
glucose, fructose, sucrose, arabinose, cellobiose, lactose,
maltose, and trehalose. Examples of the polysaccharide include
maltodextrin, oligosaccharides, inulin, gum arabic, and chitosan.
Examples of the protein include various amino acids, oligopeptides,
gelatin, water-soluble collagen, casein, and cyclodextrin.
[0052] The pH adjuster to be used may be a base such as sodium
hydroxide, an acid such as hydrochloric acid, or a buffer solution
such as a phosphate buffer solution or a citrate buffer solution.
Examples of the antioxidant include ascorbic acid, an ascorbic acid
derivative, and a citric acid monoglyceride.
[0053] The amount of the additives to be added to the aqueous phase
may be 20% by mass or less, preferably 10% by mass or less,
relative to the total mass of the aqueous phase, with the view to
finely emulsifying and dispersing. A small amount of water-soluble
organic solvent may be added to the aqueous phase in advance, as
necessary. The amount of the water-soluble organic solvent to be
added in this case is 20% by mass or less, preferably 10% by mass
or less, relative to the total mass of the aqueous phase, from the
viewpoint of the stability of the emulsion or dispersion.
[0054] [Nonionic Surfactant]
[0055] The nonionic surfactant in the invention is preferably a
nonionic surfactant having an HLB value of from 10 to 16 with the
view to improving the dispersibility, and the HLB value is more
preferably from 12 to 16 from the viewpoint of the stability of the
emulsion.
[0056] The nonionic surfactant may be contained in either one of
the organic solvent phase or the aqueous phase, or in both of the
organic solvent phase and the aqueous phase. It is preferable that
at least one nonionic surfactant is added to the organic solvent
phase. In this case, the production method according to the
invention may further include a process of adding a nonionic
surfactant to the water-soluble organic solvent solution and
uniformizing the solution, before the water-soluble organic solvent
solution is mixed with the aqueous solution.
[0057] At least one of the nonionic surfactants that can be used in
the invention is preferably a nonionic surfactant capable of
dissolving in an organic solvent, from the viewpoint of decreasing
the dispersion particle diameter. The nonionic surfactant soluble
in an organic solvent may be selected, without particular
restrictions, from nonionic surfactants that are soluble in an
organic solvent.
[0058] The HLB used herein represents hydrophilic-hydrophobic
balance generally used in the field of surfactants. It can be
calculated by using generally used calculation formula such as
Kawakami's equation. In the invention, the following Kawakami's
equation is employed.
HLB=7+11.7 log(Mw/Mo)
[0059] In the above equation, Mw represents the molecular weight of
a hydrophilic group, and Mo represents the molecular weight of a
hydrophobic group.
[0060] Alternatively, numerical values of HLB listed in
manufacture's catalogs may be used. As is apparent from the above
equation, a nonionic surfactant with any HLB value can be obtained
by utilizing the additive properties of HLB.
[0061] Examples of nonionic surfactants that may suitably be used
in the invention include (mono, di, or tri)glycerol fatty acid
esters, monoglycerol organic acid esters, polyglycerol fatty acid
esters, propylene glycol fatty acid esters, polyglycerol condensed
ricinoleic acid esters, sorbitan fatty acid esters, and sucrose
fatty acid esters. Among the above, a more preferable nonionic
surfactant in the invention is a polyglycerol fatty acid ester,
sucrose fatty acid ester, or a combination thereof, from the
viewpoint of improving the stability of the dispersion. Any one of
the nonionic surfactants may be used singly, or two or more thereof
may be used in combination at an arbitrary ratio.
[0062] The nonionic surfactant is not necessarily a highly purified
product obtained by distillation or the like, and may be a reaction
mixture.
[0063] Examples of the polyglycerol fatty acid esters include an
ester of a polyglycerol having an average degree of polymerization
of 4 or more, preferably 6 to 10, and a fatty acid having 8 to 18
carbon atoms (for example, caprylic acid, capric acid, lauric acid,
myristic acid, palmitic acid, stearic acid, oleic acid, and
linoleic acid).
[0064] Preferable examples of the polyglycerol fatty acid ester
include hexaglyceryl monopalmitate, hexaglyceryl monomyristate,
hexaglyceryl monolaurate, decaglyceryl monooleate, decaglyceryl
monostearate, decaglyceryl monopalmitate, decaglyceryl
monomyristate, and decaglyceryl monolaurate.
[0065] These polyglycerol fatty acid ester can be used singly or as
a mixture thereof.
[0066] Examples of the commercially available product of
polyglycerol fatty acid esters include NIKKOL HEXAGLYN 1-L, NIKKOL
HEXAGLYN 1-M, NIKKOL HEXAGLYN 1-L, NIKKOL DECAGLYN 1-M, NIKKOL
DECAGLYN 1-SV, NIKKOL DECAGLYN 1-50SV, NIKKOL DECAGLYN 1-ISV,
NIKKOL DECAGLYN 1-O, NIKKOL DECAGLYN 1-OV and NIKKOL DECAGLYN 1-LN
(manufactured by Nikko Chemicals Co., Ltd.); RYOTO polyglyester
L-10D, L-7D, M-10D, M-7D, P-8D, S-28D, S-24D, SWA-20D, SWA-15D,
SWA-10D and O-15D (manufactured by Mitsubishi-Kagaku Foods
Corporation); and Poem J-0381V and Poem J-0021 (manufactured by
Riken Vitamin Co., Ltd.).
[0067] The sucrose fatty acid ester to be used in the invention is
preferably one having 12 or more, more preferably from 12 to 20
carbon atoms in the fatty acid moiety.
[0068] Preferable examples of the sucrose fatty acid ester include
sucrose dioleate, sucrose distearate, sucrose monopalmitate,
sucrose monomyristate and sucrose monolaurate. In the invention,
these sucrose fatty acid esters may be used singly or may used as a
mixture thereof.
[0069] Examples of the commercially available product of sucrose
fatty acid esters include, but are not limited to, RYOTO sugar
ester S-1170, S-1170S, S-1570, S-1670, P-1570, P-1670, M-1695,
O-1570, OWA-1570, L-1695, and LWA-1570 (manufactured by
Mitsubishi-Kagaku Foods Corporation); and DK ester F140, DK ester
F160 and DK ester SS (manufactured by DAI-ICHI KOGYO SEIYAKU CO.,
LTD.).
[0070] In the invention, lecithin may be used in combination with
the water-soluble nonionic surfactant described above. The lecithin
used in the invention contains a glycerol skeleton, a fatty acid
residue, and a phosphoric acid residue as essential constituent
components, and one or more of a base, a polyhydric alcohol, or the
like are bonded thereto. The lecithin used in the invention is also
referred to as "phospholipid".
[0071] Since lecithin has a hydrophilic group and a hydrophobic
group within a molecule, lecithin has widely been used as an
emulsifying agent in the fields of foods, drugs, and cosmetics.
[0072] Industrially, products having a lecithin purity of 60% or
higher are used as lecithins, and can be used in the invention.
However, from the viewpoints of formation of fine oil droplets and
stability of the functional oil component, lecithins that are
generally called high-purity lecithins are preferable, and the
lecithin purity of the high-purity lecithins is 80% by mass or
higher, and more preferably 90% by mass or higher.
[0073] Examples of lecithins include various known lecithins that
are extracted and isolated from living bodies of plants, animals,
and microorganisms.
[0074] Specific examples of such lecithins include various
lecithins derived from, for example, plants such as soybean, Indian
corn, peanut, rapeseed, and wheat, animals such as egg yolk and
cow, and microorganisms such as Escherichia coli.
[0075] Examples of the compound names of the lecithins include
glycerolecithins such as phosphatidic acid, phosphatidylglycerol,
phosphatidylinositol, phosphatidylethanolamine, phosphatidyl
methylethanolamine, phosphatidylcholine, phosphatidylserine,
bisphosphatidic acid, and diphosphatidyl glycerol (cardiolipin),
and sphingolecithins such as sphingomyelin, and combinations
thereof.
[0076] In the invention, other than the high-purity lecithins, the
following lecithins may be used: hydrogenated lecithins,
enzymatically decomposed lecithins, enzymatically decomposed
hydrogenated lecithins, hydroxy lecithins, and combinations
thereof. Any of these lecithins, which may be used in the
invention, may be used singly, or in the form of a mixture of two
or more kinds thereof.
[0077] The amount of the nonionic surfactants to be added is
preferably from 0.1 to 50% by mass, more preferably from 0.5 to 20%
by mass, and still more preferably from 1 to 15% by mass, relative
to the total mass of the emulsion or dispersion.
[0078] The amount of the nonionic surfactants to be added is
preferably from 10 to 1000% by mass, and more preferably from 50 to
500% by mass, relative to the natural ingredient.
[0079] A nonionic surfactant addition amount of 0.1% by mass or
more makes it easy to obtain a dispersion having a fine particle
diameter, improves the stability of the obtained dispersion, and
thus is preferable. A nonionic surfactant addition amount of 50% by
mass or less is preferable since problems such as severe foaming of
the dispersion hardly occur at such an addition amount.
[0080] In addition to the water-soluble organic solvent used also
as an extracting liquid, one or more other water-soluble organic
solvents may be mixed into the water-soluble organic solvent
solution. In addition to the water-soluble organic solvent used
also as an extracting liquid, water may be added. The mixing ratio
of the water-soluble organic solvents and water added afterwards is
preferably 50% by volume or lower, and more preferably 30% by
volume or lower, relative to the total mass of the water-soluble
organic solvent solution after mixing therewith, from the viewpoint
of forming finer emulsion particles.
[0081] (Micromixer)
[0082] In the invention, a most suitable device for passing the
water-soluble organic solvent solution (hereinafter simply referred
to as "oil phase" or "water-soluble organic solvent phase" in some
cases) and the aqueous solution (hereinafter simply referred to as
"aqueous phase" in some cases) through microchannels of which
narrowest portion has a cross-sectional area of from 1 .mu.m.sup.2
to 1 mm.sup.2 and thereafter mixing them by counter collision is
counter-collision micromixer. The micromixer is generally a device
which mixes two different liquids in a microspace, one of the
liquids is an organic solvent phase containing a functional oil
component, and the other liquid is an aqueous phase which is an
aqueous solution.
[0083] The inventors have found that application of a micromixer to
preparation of an emulsion having a small particle diameter, which
is a microchemical process, exhibits relatively low energy
consumption, generates less heat, and enables provision of an
emulsion or dispersion that has substantially uniform particle
diameters and has excellent storage stability compared to usual
agitation emulsification dispersing methods or high-pressure
homogenizer emulsification dispersing methods. The inventors have
also clarified that application of a micromixer is a most suitable
method for emulsification when a natural ingredient that is
susceptible to thermal deterioration is contained.
[0084] In summary, an emulsification or dispersing method using a
micromixer includes distributing the respective aqueous oil phases
to microspaces, and contacting or colliding them in the respective
microspaces. This method is clearly different from a membrane
emulsification method or a microchannel emulsification method, in
which only one phase is distributed to microspaces and the other
phase is supplied as a bulk. Indeed, when only one phase is
distributed to microspaces, the effect of the invention cannot be
obtained. Known micromixers feature various different structures.
In terms of flow and mixing in microchannels, two kinds of method
can be exemplified: a method in which mixing is achieved while
maintaining a laminar flow, and a method in which mixing is
achieved while disturbing a flow, that is, in a turbulent flow. In
the method in which mixing is achieved while maintaining a laminar
flow, the efficiency of mixing is improved by adjusting the depth
dimension of flow channels to be larger than the width dimension of
the flow channels, increasing the interface area between the two
different liquids as far as possible, and reducing the thickness of
both layers. Alternatively, a method in which two different liquids
are alternately flowed in a multilayer flow via a
multiply-segmented inlet for the liquids has also been
proposed.
[0085] Meanwhile, a method in which mixing is achieved in a
turbulent flow is generally a method in which respective liquids
are flowed at a relatively high speed by distributing them to
narrow flow channels. A method in which one liquid is sprayed into
the other liquid that has been introduced into microspaces using an
arrayed micro-nozzle has also been proposed. Furthermore, a
particularly excellent mixing effect can be obtained in a method in
which liquids flowing at a high speed are forcibly contacted with
each other using various means. The former method using a laminar
flow generally produces particles that have large diameter but
relatively uniform particle diameter distribution. In the latter
method using a turbulent flow, there is a possibility that a very
fine emulsion is obtained, and thus the method using a turbulent
flow is preferable in many cases in view of stability and
transparency. Representative methods using a turbulent flow include
a method using a slit-interdigital-type micromixer and a method
using a collision-type micromixer. A slit-interdigital-type
micromixer, as typified by a mixer manufactured by IMM Gmbh, has a
structure in which two interdigital flow channels are faced and
arranged such that one channel enters between the two other
channels. Although a turbulent flow is caused when the width
between the slits is sufficiently small, an organic solvent phase
and an aqueous phase flow in the same direction in a parallel flow
without colliding with each other after merging. Therefore, the
forcible contacting effect in a slit-interdigital micromixer has
not been sufficient compared to a collision-type micromixer.
[0086] A collision-type micromixer, represented by a KM mixer, has
a structure in which forcible contact is conducted by utilizing
kinetic energy. Specifically, collision-type micromixers include a
central collision-type micromixer disclosed by Nagasawa et al. ("H.
Nagasawa et al., Chem. Eng. Technol., 28, No. 3, 324-330 (2005)";
JP-A No. 2005-288254). It has become evident that an extremely fine
emulsion or dispersion can be easily formed in the method of
countercurrently colliding an aqueous phase and an organic solvent
phase, since mixing time is extremely short and an oil phase
droplet is instantly formed.
[0087] In the invention, when emulsification is performed by
micro-mixing with a collision-type micromixer, it is required that
the temperature at emulsification (emulsification temperature) is
such that micro-mixing is performed at a temperature of the
aforementioned separate microspaces of the micromixer (a
temperature at micro-mixing part of the micromixer) of 80.degree.
C. or lower, preferably from 0.degree. C. to 80.degree. C. and
particularly preferably from 5.degree. C. to 75.degree. C., from
the viewpoint of uniformity of the particle diameter in the
resulting emulsion. An emulsification temperature of 0.degree. C.
or higher is preferable since a main component of the dispersing
medium is water and, therefore, the emulsification temperature can
be managed. The temperature of the microspaces of the micromixer is
preferably maintained at 100.degree. C. or lower. When the
temperature is maintained at 100.degree. C. or lower, management of
the retained temperature may be easily controlled, and the
micro-bumping phenomenon which adversely influences the
emulsification performance may be prevented. It is further
preferable that the temperature is controlled to be maintained at a
temperature of 80.degree. C. or lower.
[0088] The temperature at which the oil phase (water-soluble
organic solvent phase) that is distributed to the microspaces of
the micromixer is maintained, the temperature at which the aqueous
phase that is distributed to the microspaces of the micromixer is
maintained, and the temperature at which the microspaces of the
micromixer are maintained vary depending on the components
contained in the aqueous phase and the organic solvent phase, and
are each independently preferably from 0.degree. C. to 80.degree.
C., particularly preferably from 5.degree. C. to 75.degree. C. When
the oil phase includes a water-soluble organic solvent, the
temperature at which the oil phase that is distributed to the
microspaces of the micromixer is maintained, the temperature at
which the aqueous phase that is distributed to the microspaces of
the micromixer is maintained, and the temperature at which the
microspaces of the micromixer are maintained are each independently
preferably from 0.degree. C. to 50.degree. C., and particularly
preferably from 5.degree. C. to 25.degree. C. Although the
temperature at which the microspaces of the micromixer are
maintained, the temperature at which the oil phase and the aqueous
phase distributed to the microspaces of the micromixer are
maintained, and the temperature at which the oil phase and the
aqueous before distributed to the microspaces of the micromixer are
maintained (i.e., the temperature at which the oil phase supply
tank and the aqueous phase supply tank are maintained) may be
different from one another, they are preferably the same
temperature in the point of stability of mixing.
[0089] In the invention, it is particularly preferable that the
temperatures at which the aqueous phase and the organic solvent
phase that are distributed to the microspaces of the micromixer are
maintained before and after distribution, the temperature at which
the microspaces of the micromixer are maintained, and the
temperature at which the aforementioned separate microspaces of the
micromixer are maintained, are adjusted to a temperature higher
than ambient temperature, and an oil-in-water emulsion obtained by
the micromixer after micro-mixing and emulsification is cooled to
ambient temperature after collection.
[0090] The cross-sectional area of the narrowest part of the
microspaces (flow channels) of the micromixer in the invention is
from 1 .mu.m.sup.2 to 1 mm.sup.2 and preferably from 500
.mu.m.sup.2 to 50,000 .mu.m.sup.2, from the viewpoints of
decreasing the emulsion particle diameter and narrowing the
particle diameter distribution.
[0091] The cross-sectional area of the narrowest part of the
microspaces (flow channels) for the aqueous phase of the micromixer
in the invention is particularly preferably from 1,000 .mu.m.sup.2
to 50,000 .mu.m.sup.2 from the viewpoint of stability of
mixing.
[0092] The cross-sectional area of the narrowest portion of the
microspaces (flow channels) for the oil phase of the micromixer is
particularly preferably from 500 .mu.m.sup.2 to 20,000 .mu.m.sup.2
from the viewpoints of decreasing the emulsion particle diameter
and narrowing the particle diameter distribution.
[0093] In the present invention, when emulsifying and dispersing
with the micromixer, the flow rate of the oil phase and the aqueous
phase in emulsifying and dispersing varies depending on the
micromixer used and the flow rate of the aqueous phase is
preferably from 10 ml/min to 500 ml/min, more preferably from 20
ml/min to 400 ml/min and particularly preferably from 50 ml/min to
300 ml/min, from the viewpoints of decreasing the emulsion particle
diameter and narrowing the particle diameter distribution.
[0094] The flow rate of the oil phase is preferably from 1 ml/min
to 70 ml/min, more preferably from 3 ml/min to 60 ml/min and
particularly preferably from 7 ml/min to 40 ml/min, from the
viewpoints of decreasing the emulsion particle diameter and
stability of mixing.
[0095] The value obtained by dividing flow rates of both phases by
the cross-sectional area of a microchannel, that is, the ratio
(Vo/Vw) of flow speeds of both phases is preferably in the range
from 0.05 to 5 from the viewpoints of forming finer emulsion
particles and design of the micromixer. Here, Vo represents the
flow speed of an organic solvent phase containing a water-insoluble
natural integrant, and Vw represents the flow speed of an aqueous
phase. Furthermore, it is most preferable that the range of the
ratio (Vo/Vw) of the flow speed is from 0.1 to 3 from the viewpoint
of forming further finer emulsion particles.
[0096] In addition, the liquid sending pressure of the aqueous
phase is preferably from 50 KPa to 5000 KPa, more preferably from
100 KPa to 2000 KPa, and particularly preferably from 200 KPa to
1000 KPa; and the liquid sending pressure of the oil phase is
preferably from 10 KPa to 1000 KPa, more preferably from 20 KPa to
500 KPa, and particularly preferably from 40 KPa to 200 KPa. The
liquid sending pressure of the aqueous phase of from 50 KPa to 5000
KPa is preferable since the stable solution sending flow rate tends
to be maintained. The liquid sending pressure of the oil phase of
from 10 KPa to 1000 KPa is preferable, since the uniform mixing
property tends to be obtained.
[0097] In the invention, the flow rate, the solution sending
pressure and the maintained temperature are more preferably a
combination of respective preferably examples.
[0098] Next, a pathway from introduction of the aqueous phase and
the oil phase into the micromixer until discharge thereof as an O/W
emulsion is explained using the example of a microdevice (FIG. 1)
as one example of the micromixer in the invention.
[0099] As shown in FIG. 1, a microdevice 100 consists of supply
element 102, a confluence element 104 and a discharge element 106,
each having a cylindrical form.
[0100] On a surface of the supply element 102 facing the confluence
element 104, annular channels 108 and 110 each having rectangular
cross-sectional shape are arranged in a concentric pattern as
channels for the oil phase or the aqueous phase of the invention.
In the supply element 102, bores 112 and 114 are formed leading to
each annular channel, penetrating in a thickness (or height)
direction.
[0101] In the confluence element 104, bores 116 are formed
penetrating in a thickness direction. These bores 116 are arranged
such that when the elements are fastened to one another to form the
microdevice 100, ends 120 of the bores 116 located on a surface of
the confluence element 104 facing the supply element 102 open into
the annular channel 108. In an embodiment shown in the drawing,
four bores 116 are formed, and they are arranged equiangularly to
the annular channel 108.
[0102] In the confluence element 104, bores 118 penetrating in a
thickness direction are formed similarly to the bores 116. The
bores 118 are formed such that they open into the annular channel
110, as well as the bores 116. The bores 118 are arranged
equiangularly to the annular channel 110, and the bores 116 and the
bores 118 are alternately-arranged.
[0103] On a surface 122 of the confluent element 104 facing the
discharge element 106, the microchannels 124 and 126 are formed.
One end of each of these microchannels 124 or 126 is an opening
part of the bores 116 or 118, and the other end is a central part
128 of the surface 122. All microchannels extend from bores towards
this central part 128, and converge at a center. A cross-sectional
shape of the microchannels may be, for example, a rectangular
shape.
[0104] In the discharge element 106, a bore 130 is formed passing a
center thereof and penetrating in a thickness direction. Therefore,
this bore is opened into the central part 128 of the confluence
element 104 at one end, and is opened to the outside of the
microdevice at the other end.
[0105] In the present microdevice 100, fluids A and B supplied from
the outside of the microdevice 100 at ends of bores 112 and 114 are
flown into annular channels 108 and 110 via bores 112 and 114,
respectively.
[0106] The annular channel 108 and the bores 116 are communicated,
and the fluid A flown into the annular channel 108 enters
microchannels 124 via the bores 116. In addition, the annular
channel 110 and the bores 118 are communicated, and the fluid B
flown into the annular channel 110 enters microchannels 126 via the
bores 118. Fluids A and B are flown into microchannels 124 and 126,
respectively, and are flown towards a central part 128, and are
converged.
[0107] The converged fluids are discharged as a stream C to the
outside of the microdevice via the bore 130.
[0108] The following variations of the microdevice 100 may be
used.
[0109] Annular channel 108: cross-sectional
shape/width/depth/diameter: rectangular shape/1.5 mm/1.5 mm/25
mm
[0110] Annular channel 110: cross-sectional
shape/width/depth/diameter: rectangular shape/1.5 mm/1.5 mm/20
mm
[0111] Bore 112: diameter/length: 1.5 mm/10 mm (circular
cross-section)
[0112] Bore 114: diameter/length: 1.5 mm/10 mm (circular
cross-section)
[0113] Bore 116: diameter/length: 0.5 mm/4 mm (circular
cross-section)
[0114] Bore 118: diameter/length: 0.5 mm/4 mm (circular
cross-section)
[0115] Microchannel 124: cross-sectional
shape/width/depth/length/cross-sectional area: rectangular
shape/350 .mu.m/100 .mu.m/12.5 mm/35,000 .mu.m.sup.2
[0116] Microchannel 126: cross-sectional
shape/width/depth/length/cross-sectional area: rectangular shape/50
.mu.m/100 .mu.m/10 mm/5,000 .mu.m.sup.2
[0117] Bore 130: diameter/length: 500 .mu.m/10 mm (circular
cross-section)
[0118] The size of the microchannels (124 and 126 in FIG. 1) at
which the aqueous phase and the organic solvent phase are collided
is defined in the preferable range in context with flow rates of
the aqueous phase and the organic solvent phase.
[0119] In the production method of the invention, it is preferable
that, after emulsifying and dispersing, the water-soluble organic
solvent having been used is removed via the microchannels. Examples
of the methods of removing the solvent include an evaporation
method using a rotary evaporator, a flash evaporator or an
ultrasound atomizer, and a membrane separation method using an
ultrafiltration membrane or a reverse osmosis membrane, and an
ultrafiltration membrane method is particularly preferable.
[0120] An ultra filter (UF) is an apparatus in which a stock
solution (an aqueous solution that is a mixture of water, a
high-molecular substance, a low-molecular substance, a colloidal
substance, and the like) having been pressurized is injected,
separated into two types of solutions, namely, a filtrate (the
low-molecular substance) and a concentrate (the high-molecular
substance or colloidal substance) and then taken out.
[0121] An ultrafiltration membrane is a typical asymmetric membrane
produced by the Loeb-Souriraj an method. Examples of polymer
materials that can be used for ultrafiltration membrane include
polyacrylonitrile, polyvinyl chloride-polyacrylonitrile copolymer,
polysulfone, polyether sulfone, vinylidene fluoride, aromatic
polyamide, cellulose acetate and the like. In recent years, ceramic
membranes have also been employed. Different from the reverse
osmosis method and the like, no pre-treatment is performed in the
ultrafiltration method, which causes fouling, that is, the
deposited of the polymers or the like on the membrane surface.
Therefore, it is a common to practice to wash the membrane with a
chemical or hot water at regular intervals. Thus, the membrane
material should be resistant to chemicals and heat. There are
carious membrane modules types of an ultrafiltration membrane such
as a flat membrane type, a tubular type, a hollow fiber type and a
spiral type. The performance of an ultrafiltration membrane is
indicated in a molecular weight cut off, and various membranes
having a molecular weight cut off of from 1,000 to 300,000 are
commercially available. Examples of the commercially available
membrane modules include, but are not limited to, MICROSA UF (Asahi
Kasei Chemicals Corporation), capillary-type element NTU-3306
(Nitto Denko Corporation) and the like.
[0122] To remove the solvent from the emulsion of the present
invention, the material of a membrane is particularly preferably
polysulfone, polyether sulfone or aromatic polyamide, from the
viewpoint of resistance for solvents. With respect to the membrane
module form, flat membranes are mainly employed on the laboratory
scale, while membranes of the hollow fiber type and spiral type are
employed industrially. In particular, hollow fiber type membranes
are preferable. Although the molecular weight cut off varies
depending on the kind of the active ingredient, membranes having
molecular weight cut off of in the range of from 5,000 to 100,000
are commonly used.
[0123] Although the available operation temperature is from
0.degree. C. to 80.degree. C., a temperature range of 10.degree. C.
to 40.degree. C. is particularly preferable in view of degradation
of the active ingredient.
[0124] Examples of the laboratory-scale ultrafiltration apparatuses
include flat membrane-type module ADVANTEC-UHP (ADVANTEC),
flow-type labo-test unit RUM-2 (Nitto Denko Corporation), and the
like. An industrial plant can be constructed by combining the
individual membrane modules in any number and size to satisfy the
required depending capacity. As a bench-scale unit, RUW-5A (Nitto
Denko Corporation) and the like are commercially available.
[0125] In the production method of the invention, it is preferable
to concentrate the emulsion after removing the solvent. For the
concentration, the same method and device as those described with
respect to removing the solvent, that is, the evaporation method,
the filtration method or the like, and the devices for these
methods, can be used. In the concentration, it is also preferable
to employ the ultra-filtration method. Although it is preferable to
use, if possible, the same membrane as in the solvent removal,
ultrafiltration membranes having a different molecular weight cut
off may be used if required. It is also possible to conduct the
concentration at a different temperature from the solvent removal
so as to elevate the concentration efficiency.
[0126] The emulsion obtained by the production method according to
the present invention is an oil-in-water type emulsion. From the
viewpoint of the transparency of the obtained emulsion, the
volume-average particle diameter (median diameter) of the oil
droplets in the emulsion is preferably 200 nm or less, more
preferably from 1 nm to 100 nm, and still more preferably from 1 nm
to 50 nm.
[0127] The aqueous dispersion a solid obtained by the production
method according to the invention is an aqueous solid dispersion.
From the viewpoint of the transparency of the obtained dispersion,
the volume-average particle diameter (median diameter) of the
hydrophobic solid microparticles (dispersed particles) is
preferably 200 nm or less, more preferably from 1 nm to 100 nm, and
still more preferably from 1 nm to 50 nm.
[0128] The particle diameter of the emulsified or dispersed
particles of the invention can be measured with a commercially
available particle diameter distribution measuring device or the
like. Known examples of the method of measuring the particle
diameter distribution include a optical microscopy method, a
confocal laser microscopy method, an electron microscopy method, an
atomic force microscopy method, a static light scattering method, a
laser diffraction method, a dynamic light scattering method, a
centrifugal precipitation method, an electric pulse measurement
method, a chromatography method, an ultrasonic damping method and
the like, and devices corresponding to the respective principle are
commercially available.
[0129] In consideration of the volume-average particle diameter
range in the invention and ease of measurement, the dynamic light
scattering method is preferable for measuring the volume-average
particle diameter of the emulsion or dispersion of the invention.
Examples of the commercially available measurement devices using
dynamic light scattering include NANOTRAC UPA (Nikkiso Co., Ltd.),
a dynamic light scattering particle diameter distribution measuring
device LB-550 (Horiba, Ltd.), a thick type particle diameter
analyzer FPAR-1000 (Otsuka Electronics Co., Ltd.) and the like.
[0130] In the invention, the volume-average particle diameter is
measured by using the dynamic light scattering particle diameter
distribution measuring device at 25.degree. C.
[0131] The emulsion or dispersion obtained according to the
invention is a fine emulsion or dispersion in which deterioration
of the quality of the natural ingredient is remarkably reduced.
Therefore, the emulsion or dispersion is favorably used for various
applications depending on the types of the natural ingredients.
[0132] Examples of the applications include foods, skin external
preparations, and drugs.
[0133] That is, a food according to the invention is a food
containing an emulsion or dispersion obtained according to the
production method described above, and the natural ingredient is a
functional food ingredient. The functional food ingredient may be
any of the natural ingredients described above that is usable in
food applications, and specific examples thereof include, but are
not limited to, terpenoids and polyphenols.
[0134] A skin external preparation according to the invention is a
skin external preparation containing an emulsion or dispersion
obtained according to the above production method, wherein the
natural ingredient described above is a skin external preparation
ingredient. The skin external preparation ingredient may be any of
the above-described natural ingredients that is usable in skin
external applications, and specific examples thereof include, but
are not limited to, fatty acids, complex lipids, and
terpenoids.
[0135] A drug according to the invention is a drug containing an
emulsion or dispersion obtained according to the above production
method, wherein the natural ingredient is a pharmaceutical
ingredient. The pharmaceutical ingredient may be any of the
above-described natural ingredients that is usable in
pharmaceutical applications, and specific examples thereof include,
but are not limited to, alkaloids and steroids.
EXAMPLES
[0136] The present invention is described more specifically below
by reference to examples. In the description below, "part(s)" and
"%" are based on mass unless indicated otherwise.
Example 1
Preparation of Emulsion A
[0137] 280 g of pure water was prepared as a water phase A.
[0138] Further, the following components were dissolved at
65.degree. C. for 1 hour, and thereafter cooled to 25.degree. C.,
whereby an oil phase A was obtained.
TABLE-US-00001 Haematococcus algae extract 0.6 g (content of
astaxanthins: 10% by mass): Mixed tocopherol: 0.1 g Sucrose
stearate (HLB = 15): 0.3 g Decaglyceryl monooleate (HLB = 12): 0.3
g Ethanol: 38.4 g
[0139] Here, the sucrose stearate used was RYOTO Sugar Ester S-1670
(HLB=15) manufactured by Mitsubishi-Kagaku Foods Corp., and the
decaglyceryl monooleate used was NIKKOL DECAGLYN 1-O (HLB-12)
manufactured by Nikko Chemicals Co. Ltd. The Haematococcus algae
extract used was ASTOTS-10O manufactured by Takeda Shiki Co., Ltd.
The Haematococcus algae extract was a product in the form of an
isolated dried oily material. The mixed tocopherol used was REKEN E
OIL 800 manufactured by Riken Vitamin Co., Ltd. The ethanol used
was a special grade reagent manufactured by Wako Pure Chemical
Industries Ltd.
[0140] A slit-interdigital SSIMM-SS-Ni25 (manufactured by IMM
Gmbh), in which 5 .mu.m sintered metal filters were provided at
respective flow channels, was prepared as the micromixer to be used
for emulsification, and all of the micromixer, the aqueous phase A,
and the oil phase A were placed in an environment of 25.degree.
C.
[0141] A precision metering pump was set to provide an aqueous
phase flow rate of 21.0 ml/min and an oil phase flow rate of 3.0
ml/min, and the aqueous phase and the oil phase were respectively
introduced into the micromixer to perform micro-mixing.
[0142] Subsequently, an emulsion was sampled when the flow rates
and the liquid feeding pressures became stable, and the emulsion is
referred to as astaxanthin-containing emulsion A. The particle
diameters of the oil droplets of the emulsion A were measured with
a FPAR1000 particle size analyzer manufactured by manufactured by
Otsuka Electronics Co., Ltd., and the median diameter thereof was
found to be 135 nm.
Preparation of Emulsion B
[0143] The compositions of the aqueous phase and the oil phase, and
the preparation methods were exactly the same as in the case of the
emulsion A; however, a KM-type micromixer 100/100, which is a
counter-collision micromixer, was used as the micromixer used for
emulsification. In this micromixer, the microchannels for
pre-collision liquids, i.e., the microchannels 124 and the
microchannels 126 in FIG. 1, have rectangular shapes and the
following sizes:
[0144] Microchannel 124: width/depth/length: 100 .mu.m/100
.mu.m/12.5 mm
[0145] Microchannel 126: width/depth/length: 100 .mu.m/100 .mu.m/10
mm
[0146] Emulsification was performed in the same manner as in the
case of the emulsion A, except that this micromixer was used for
the emulsification while introducing the aqueous phase to the outer
annular channel at a flow rate of 21.0 ml/min and introducing the
oil phase to the inner annular channel at a flow rate of 3.0
ml/min. As a result, an emulsion B was obtained. The median
diameter of the oil droplets of the emulsion B was 45 nm.
Preparation of Emulsion C
[0147] The compositions of the aqueous phase and the oil phase, and
the preparation methods were exactly the same as in the case of the
emulsion A; however, a KM-type micromixer 350/50 was used as the
micromixer used for emulsification. In this micromixer, the
microchannels for pre-collision liquids, i.e., the microchannels
124 and the microchannels 126 in FIG. 1, have rectangular shapes
and the following sizes:
[0148] Microchannel 124: width/depth/length: 350 .mu.m/100
.mu.m/12.5 mm
[0149] Microchannel 126: width/depth/length: 50 .mu.m/100 .mu.m/10
mm
[0150] Emulsification was performed in the same manner as in the
case of the emulsion A, except that this micromixer was used for
the emulsification while introducing the aqueous phase to the outer
annular channel (microchannels 124) at a flow rate of 42.0 ml/min
and introducing the oil phase to the inner annular channel
(microchannels 126) at a flow rate of 6.0 ml/min. As a result, an
emulsion C was obtained. The median diameter of the oil droplets of
the emulsion C was 19 nm.
Preparation of Emulsion D
[0151] The compositions of the aqueous phase and the oil phase, and
the preparation methods were exactly the same as in the case of the
emulsion C, and the micromixer used for emulsification was the
KM-type micromixer 350/50. However, unlike the emulsion C, the flow
rate of the aqueous phase introduced to the inner annular channel
(microchannels 126) was 42.0 ml/min, and the flow rate of the oil
phase introduced to the outer annular channel (microflow channels
124) was 6.0 ml/min. Except for these points, emulsification was
performed in the same manner as in the case of the emulsion C,
whereby an emulsion D was obtained. The median diameter of the oil
droplets of the emulsion D was 95 nm.
Preparation of Emulsion E
[0152] The compositions of the aqueous phase and the oil phase, and
the preparation methods were exactly the same as in the case of the
emulsion A; however, a KM-type micromixer 200/100 was used as the
micromixer used for emulsification. In this micromixer, the
microchannels for pre-collision liquids, i.e., the microchannels
124 and the microchannels 126 in FIG. 1, have rectangular shapes
and the following sizes:
[0153] Microchannel 124: width/depth/length: 200 .mu.m/100
.mu.m/12.5 mm
[0154] Microchannel 126: width/depth/length: 100 .mu.m/100 .mu.m/10
mm
[0155] Emulsification was performed in the same manner as in the
case of the emulsion A, except that this micromixer was used for
the emulsification while introducing the aqueous phase to the outer
annular channel (microchannels 124) at a flow rate of 31.5 ml/min
and introducing the oil phase to the inner annular channel
(microchannels 126) at a flow rate of 4.5 ml/min. As a result, an
emulsion E was obtained. The median diameter of the oil droplets of
the emulsion E was 28 nm.
Preparation of Emulsion F
[0156] The compositions of the aqueous phase and the oil phase, and
the preparation methods were exactly the same as in the case of the
emulsion E, and the micromixer used for emulsification was the
KM-type micromixer 200/100. However, unlike the emulsion E, the
flow rate of the aqueous phase introduced to the inner annular
channel (microchannels 126) was 31.5 ml/min, and the flow rate of
the oil phase introduced to the outer annular channel (microflow
channels 124) was 4.5 ml/min. Except for these points,
emulsification was performed in the same manner as in the case of
the emulsion E, whereby an emulsion F was obtained. The median
diameter of the oil droplets of the emulsion F was 55 nm.
Preparation of Emulsion G
[0157] The aqueous phase A and the oil phase A were mixed with a
stirrer so as to provide a mixture having the same composition as
that of the emulsion A, and, immediately thereafter, emulsification
was performed for 5 min using an agitation-type homogenizer
(manufactured by Nippon Seiki Co., Ltd.) at 10000 rpm, as a result
of which an astaxanthin-containing emulsion G was obtained. The
median diameter of the oil droplets of the emulsion G was 347
nm.
Preparation of Emulsion H
[0158] Haematococcus pluvialis alga containing astaxanthin was
cooled to -50.degree. C., and dehydrated by freeze drying. Then,
sodium chloride was added thereto, and pulverization operation was
performed. As a result, fine powder of the Haematococcus alga was
obtained. The Haematococcus alga fine powder was immersed in
ethanol in a refrigerator for 24 hours, so that astaxanthin was
extracted from the Haematococcus alga.
[0159] Ethanol was added to the extract such that the absorbance of
the extract liquid at 478 nm became the same as that of the oil
phase A. The mixed tocopherol, the sucrose stearate, and the
decaglyceryl monooleate were added to and dissolved in the obtained
Haematococcus alga ethanol extract liquid such that the respective
components have the same compositional ratios as those of the
corresponding components in the oil phase A. As a result, an oil
phase H was obtained.
[0160] The oil phase H and the aqueous phase A were subjected to
micromixer emulsification in exactly the same manner as in the case
of the emulsion A, whereby an emulsion H was obtained. The median
diameter of the oil droplets of the emulsion H was 120 nm.
Preparation of Emulsion I
[0161] Preparation was performed in the same manner as in the case
of the emulsion B, except that the oil phase H was used in place of
the oil phase A. The median diameter of the oil droplets of the
emulsion I was 37 nm.
Preparation of Emulsion J
[0162] Preparation was performed in the same manner as in the case
of the emulsion C, except that the oil phase H was used in place of
the oil phase A. The median diameter of the oil droplets of the
emulsion J was 12 nm.
Preparation of Emulsion K
[0163] Preparation was performed in the same manner as in the case
of the emulsion D, except that the oil phase H was used in place of
the oil phase A. The median diameter of the oil droplets of the
emulsion K was 89 nm.
Preparation of Emulsion L
[0164] Preparation was performed in the same manner as in the case
of the emulsion E, except that the oil phase H was used in place of
the oil phase A. The median diameter of the oil droplets of the
emulsion L was 26 nm.
Preparation of Emulsion M
[0165] Preparation was performed in the same manner as in the case
of the emulsion F, except that the oil phase H was used in place of
the oil phase A. The median diameter of the oil droplets of the
emulsion M was 54 nm.
Preparation of Emulsion N
[0166] Preparation was performed in the same manner as in the case
of the emulsion G, except that the oil phase H was used in place of
the oil phase A. The median diameter of the oil droplets of the
emulsion N was 330 nm.
[0167] Each of the emulsions A to N were processed using a
laboratory-scale ultrafiltration apparatus ADVANTEC-UHP-43K with an
ultrafiltration membrane Q0500043E (50000 Da) made of polysulfone,
thereby removing ethanol to a content of 0.1%; further,
concentration operation was performed using the same apparatus,
thereby concentrating the emulsion until the astaxanthin content
became 1.0%. As a result, concentrated emulsions A to N were
obtained.
[0168] Each of the concentrated emulsions A to N were evaluated by
ten people, including men and women, with respect to the presence
or absence of odor, and was graded - (acceptable level), +
(somewhat uncomfortable level), and ++ (problematic level).
[0169] Each of the emulsions was stored at 50.degree. C. for 21
days, and a residual colorant ratio was measured. The residual
colorant ratio was determined by measuring, using a
spectrophotometer, the absorbance of a liquid that was obtained by
diluting the emulsion before storage 3,000 times with pure water
and the absorbance of a liquid that was obtained by diluting the
emulsion after storage 3,000 times with pure water, and obtaining a
ratio of the absorbance at 478 nm after storage to the absorbance
at 478 nm before storage.
[0170] The results with respect to the oil droplet diameter, the
evaluation on odor, and the residual colorant ratio obtained by
storage at 50.degree. C. for 21 days are summarized in Table 1.
TABLE-US-00002 TABLE 1 Preparation Conditions Evaluation Results
Oil Phase Aqueous Phase Oil Droplet Residual Between Microflow
Channel Microflow Channel Median Colorant Ratio Extraction and
Cross-sectional Cross-sectional Diameter After 50.degree. C. Sample
Emulsification Emulsification Apparatus Area (.mu.m.sup.2) Area
(.mu.m.sup.2) Vo/Vw (nm) Odor for 21 days (%) A Once Dried
Slit-interdigital micro 625 625 0.14 135 + 85 B Once Dried
Counter-collision micro 10000 10000 0.14 45 + 76 C Once Dried
Counter-collision micro 5000 35000 1.00 19 + 62 D Once Dried
Counter-collision micro 35000 5000 0.02 95 + 83 E Once Dried
Counter-collision micro 10000 20000 0.29 28 + 64 F Once Dried
Counter-collision micro 20000 10000 0.07 55 + 81 G Once Dried
Stirring-type homogenizer -- -- -- 347 ++ 77 H Continuous
Slit-interdigital micro 625 625 0.14 120 - 90 I Continuous
Counter-collision micro 10000 10000 0.14 37 - 92 J Continuous
Counter-collision micro 5000 35000 1.00 12 - 93 K Continuous
Counter-collision micro 35000 5000 0.02 89 - 95 L Continuous
Counter-collision micro 10000 20000 0.29 26 - 92 M Continuous
Counter-collision micro 20000 10000 0.07 54 - 93 N Continuous
Stirring-type homogenizer -- -- -- 330 + 88
[0171] As shown in FIG. 1, use of a counter-collision micromixer
enabled formation of drastically finer emulsion with high
transparency, as compared to cases in which a stirring-type
emulsification apparatus or a slit-interdigital micromixer was
used. Emulsions B to F are reference examples, and emulsions I to M
belong to the present invention.
[0172] Although the same astaxanthin extracted from Haematococcus
algae were used, the emulsions B to F, the preparation of which
includes once isolating the astaxanthin as a dried oily product and
dissolving it in ethanol to form an oil phase, exhibited
uncomfortable odor and inferior storage stability of the
astaxanthin colorant when storing over time. In contrast, it was
clearly demonstrated that the emulsions I to M, the oil phase of
which was formed through a continuous process without drying and
solidifying the liquid obtained by ethanol extraction of
astaxanthin from Haematococcus algae, exhibited ameliorated odor
and improved storage stability of the astaxanthin.
[0173] Further, when emulsification was performed using a
once-dried oily astaxanthin as a raw material, there is a tendency
for a smaller diameter of emulsion oil droplets to cause somewhat
inferior temporal stability. However, when emulsification was
performed using a raw material that had been prepared through a
continuous process without drying and solidifying the extract
liquid, a further decrease in emulsion oil droplet diameter was
enabled while maintaining the temporal stability of the astaxanthin
at a favorable level (the emulsions I to M).
[0174] As demonstrated above, a fine emulsion or dispersion of a
natural ingredient extracted from an animal or plant by using a
water-soluble organic solvent is provided with extremely small
deterioration of the quality of the natural ingredient, according
to the invention.
[0175] The disclosure of Japanese Patent Application No.
2007-260335 is incorporated herein by reference in its
entirety.
[0176] All publications, patent applications, and technical
standards mentioned in this specification are herein incorporated
by reference to the same extent as if each individual publication,
patent application, or technical standard was specifically and
individually indicated to be incorporated by reference.
* * * * *